Introduction: The events of September 11, 2001, and the deliberate bioterrorism attack with anthrax that followed, led to profound changes in the biologic research and public health agenda of the United States. The recognition that the United States was vulnerable to international terrorism, and the tremendous impact that a relatively limited biologic weapons attack had on the nation, resulted in major changes in the research focus of government, academic, and commercial entities. Ml AID understood that the United States lacked the research capacity and infrastructure to respond to the threat posed by biological weapons and emerging infectious diseases. The Regional Centers for Excellence in Biodefense and Emerging Infectious Diseases Research (RCE) program was a central component of the NIAID response to this threat, and was designed to jumpstart research in biodefense within each of the 10 public health service regions of the U.S. In 2003, Washington University in Saint Louis, Saint Louis University, the University of Missouri, Case Western Reserve University, and the Midwest Research Institute received funding to establish the Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Diseases Research (MRCE) to support research on biodefense in Region VII (Iowa, Kansas, Missouri and Nebraska) and parts of Ohio. The goals of the MRCE were consonant with the goals of the RCE program: harness the best scientists in the region for discovery and translational research designed to lead to the next generation of therapeutics, diagnostics and vaccines for biological threats; provide training and career support to create a new generation of scientists working in this field; establish core facilities to support researchers throughout the region; and develop an emergency response plan that can rapidly bring to bear our scientific expertise and research capacity in the event of any new biological threat to the region, the nation or the world. Over the past 5 years the MRCE has made significant progress towards each of those goals, and we will detail our accomplishments in subsequent sections. Given the scope of the program, and our aspirations, it is not surprising that much remains to be done. While the fundamental goals of the MRCE remain the same, this competitive renewal is built upon a research landscape that has been transformed by the RCE program. When we prepared the MRCE proposal 5 years ago, there was strength in basic immunology and in microbial pathogenesis research at the partner institutions, but relatively little was focused on the NIAID priority pathogens. Research collaborations between the MRCE partner institutions did not exist on any substantive level, and even intra-institutional collaborations in this research area were limited. There was no pipeline of young scientists and clinicians interested in research careers in biodefense, and there were no established biosafety training programs within the region. The MRCE now coordinates and supports a vibrant, highly collaborative and closely integrated group that has become the face of biodefense and emerging infectious diseases research throughout most of Region VII. MRCE programs have created a pool of talented young investigators interested in biodefense and emerging infectious diseases research. We have trained nearly 100 individuals to work safely at BSL3, and have educated investigators and public health officials throughout the country. The MRCE has responded to three separate regional emergencies, and has become an integral part of the disaster planning process for a significant part of our region. We have more than doubled the number of participating institutions, and have supported researchers from 10 different academic or industrial organizations. Most importantly, MRCE investigators made seminal basic science and translational discoveries leading to new therapeutic targets for West Nile, Dengue fever, pneumonic plague, Ebola, poxviruses, and a wide sector of RNA and DNA viruses (section A.3). We also initiated a pioneering collaborative effort in pathogen discovery and assessment that led to the recognition of 7 new viruses, one of which (WU polyomavirus), may be an important cause of respiratory disease in children. In our original application 5 years ago, we discussed how one could best assess the impact of a complex and wide ranging program like the MRCE on the research effort in Region VII. We proposed then that the most objective measure would be the change in extramural funding for biodefense and EID research in Region VII (excluding MRCE funds) during the course of the MRCE program. Since 2002, (the baseline pre-MRCE year) total extramural funding for biodefense and EID research (excluding MRCE and regional laboratory allocations) in Region VII has increased more than 2.5 fold, with the greatest increases in 2006 and 2007 despite a flat NIH budget. We believe the MRCE program has had a significant impact on Region VII and the nation, and are committed to continuing this important work.